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Tivozanib (AV-951) is an oral VEGF receptortyrosine kinase inhibitor. It has completed a pivotal Phase 3 investigation for the treatment of first line (treatment naive) patients with renal cell carcinoma.[1] The results from this first line study did not lead to FDA approval, but Tivozanib was approved by the EMA in August 2017[2]

Originally developed at Kirin Brewery, in January 2007 AVEO Pharmaceuticals acquired an exclusive license to develop and commercialize tivozanib in all territories outside of Asia.

In 2010, orphan drug designation was assigned in the E.U. for the treatment of renal cell carcinoma. In 2011, the compound was licensed to Astellas Pharma and AVEO Pharmaceuticals on a worldwide basis for the treatment of cancer

Tivozanib is an orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3 with potential antiangiogenic and antineoplastic activities. Tivozanib binds to and inhibits VEGFRs 1, 2 and 3, which may result in the inhibition of endothelial cell migration and proliferation, inhibition of tumor angiogenesis and tumor cell death. VEGFR tyrosine kinases, frequently overexpressed by a variety of tumor cell types, play a key role in angiogenesis.

Tivozanib was originally developed by Kyowa Hakko Kirin and in 2007 AVEO Pharmaceutical acquired all the rights of the compound outside Asia. In December 2015, AVEO reached an agreement with EUSA Pharma, which acquired exclusive rights to tivozanib for advanced renal cell carcinoma in Europe, South America, Asia, parts of the Middle East and South Africa.

Tivozanib is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 for first-line treatment of patients with advanced renal cell carcinoma in advanced disease or without VEGFR and mTOR inhibitors and progression after cytokine therapy Advanced renal cell carcinoma patients. Fotivda® is an oral capsule containing 890 μg and 1340 μg of Tivozanib per tablet. The recommended dose is 1 day, each 1340μg, taking three weeks, withdrawal for a week.

CAS HCL HYDRATE 682745-41-1

ティボザニブ塩酸塩水和物;

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC.

Tivozanib is synthesized in three main steps using well defined starting materials with acceptable specifications.
Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented. The critical process parameters are duly justified, methodology is presented and control is adequate.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised.
The active substance is packaged in a low-density polyethylene (LDPE) bag which complies with the EC
directive 2002/72/EC and EC 10/2011 as amended.

Product details

NAME

Fotivda

AGENCY PRODUCT NUMBER

EMEA/H/C/004131

ACTIVE SUBSTANCE

tivozanib

INTERNATIONAL NON-PROPRIETARY NAME(INN) OR COMMON NAME

tivozanib hydrochloride monohydrate

THERAPEUTIC AREA

Carcinoma, Renal Cell

ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CODE

L01XE

Publication details

MARKETING-AUTHORISATION HOLDER

EUSA Pharma (UK) Limited

REVISION

0

DATE OF ISSUE OF MARKETING AUTHORISATION VALID THROUGHOUT THE EUROPEAN UNION

Results

Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in median PFS compared to sorafenibbut showed an inferior overall survival rate of the experimental arm versus the control arm.[5][6] The Food and Drug Administration‘s Oncologic Drugs Advisory Committee voted in May 2013 13 to 1 against recommending approval of tivozanib for renal cell carcinoma. The committee felt the drug failed to show a favorable risk-benefit ratio and questioned the equipose of the trial design, which allowed control arm patients who used sorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to sorafenib. The application was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies.[6]

In 2016 AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on Overall Survival in the Pivotal PhIII trial[7]

In 2016 AVEO Oncology announced the start of a second Pivotal PhIII clinical study in Third Line advanced RCC patients. [8]

In 2016 EUSA Pharma and AVEO Oncology announced that Tivozanib had been submitted to the European Medicines Agency for review under the Centralised Procedure. [9]

In June 2017 the EMA Scientific Committee recommended Tivozanib for approval in Europe, with approval expected in September.[10]

In August 2017 the European Commission (EC) formally approved Tivozanib in Europe.[11]

■ A New and Practical Synthesis of Tivozanib

Abstract

New and improved synthetic route of tivozanib is described on a hectogram scale. An reduction cyclization process to prepare the key intermediate 6,7-dimethoxyquinolin-4-ol from the 3-(dimethylamino)-1-(2-nitrophenyl)prop-2- en-1-one compound at H2/Ni condition is adopted in good result. Commercial available materials, simple reaction and operation are used, including nitration, condensation, hydrogenation, chlorination and so on, to give the final product in 28.7% yield over six steps and 98.9% purity (HPLC).

3, 4-Dimethoxyacetophenone (1 500 g) was dissolved in 5:: L 0 ° C of 17% nitric acid (1400 g), and 67% nitric acid (843 0 g) and sodium nitrite g) at a temperature of 5 to 10 ° C. over a period of 2 to 3 hours. After completion of dropping, the mixture was stirred at 5 to 10 ° C. for 1 to 2 hours. Cold water (7. 5 L) was added and after stirring for 30 minutes, filtration and washing with water (30 L). The filtrate was added to water (7. 5 L), neutralized with sodium bicarbonate water, filtered, and washed with water (7 L). The filtrate was dried under reduced pressure to obtain 3, 4-dimethoxy-6-nitroacetophenone (2164 g) (yield = 87.9%).

The synthesis of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl} -N’- (5-methyl-3- isoxazole-yl) urea (2d) The 100 ml of N,N-dimethylformamide, 5.0g (0.051mol) of 3-amino-5- methylisoxa -zole, 7.98 g (0.051mol) of phenyl chloroformate and 17g (0.051mol) compound 2c were added to the 250 ml of three bottles. The mixture was refluxed about 5 h, cooled to room temperature, added the 100 ml of anhydrous ethanol. The obtained mixture was stirred 1 h and filtrated. The filtered product was slurried in water for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give the 20.0g white crystal compound 2d (C22H19ClN4O5) with the yield of 86.1% and the purity of more than 98.5 %. 1H-NMR (DMSO-d6/ppm): δ 2.37 (s,3H), 3.92 (s,3H), 3.94 (s,3H), 6.50 (s,1H), 6.54 (d,1H), 7.26 (dd,1H), 7.39 (s,1H), 7.48 (s,1H), 7.51 (d,1H), 8.23 (d,1H), 8.49 (d,1H), 8.77 (s,1H), 10.16(s,1H). ESI-MS: 456 (M+ +1).

Conclusions Tivozanib was synthesized through the cyclization, chlorinated, condensation reaction with 2-amino-4,5-dimethoxy acetophenone as the starting material. The total yield was 47.5% and the product purity of more than 98.5 %. The synthetic routs and methods of tivozanib are feasible to industrial production owing to the cheap raw materials, mild reaction conditions, stable technology and high yield.

Said 4-chloro-6, 7-dimethoxy-quinoline is obtained by the following synthesis method: A mixture of 100mL of toluene, 10 6g 6, 7- dimethoxy-4-quinolone and 15g trichloride phosphorus is added to 250mL three-necked flask and heated at reflux for 2h, cooled suction filtration, and dried to give an off-white powder 9. 3g 4- chloro-6, 7-dimethoxy quinoline, a yield of 87.6%, the reaction formula:

The 2-amino-4,5-dimethoxy acetophenone is synthesized by the following method: In the 250mL three-neck flask, was added 36mL of water and 7g reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g 3, 4-dimethoxy-6-nitroacetophenone, stirred for 3h, filtered off with suction, the filtrate was cooled to give a yellow powder 7g of 2-amino-4,5-dimethoxy acetophenone, yield 96 %, the reaction is:

2. The synthesis method according to claim 1, wherein: said 3,4-dimethoxy-6-nitroacetophenone is 3, 4-dimethoxy acetophenone nitration obtained by a reaction of reaction formula:

3. The method of synthesis according to claim 2, wherein: said 3,4-dimethoxy acetophenone in the catalyst, to give the phthalimido ether is reacted with acetyl chloride by Friedel The reaction is:

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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